(1) Field of the Invention
The present invention relates to an improvement to vaccines containing alum in their compositions and in which the antigen can be partially or completely absorbed on alum. The improvement consists in the combining in the composition constituting these vaccines of 2 to 120 .mu.g per kg body weight, or 0.1 to 6 mg per dose, of muramyl peptide; these vaccines thus improved have, in particular, the advantage of conferring an enhanced immunity, so that the number of injections needed for the immunization is reduced. The only immunoadjuvants currently used in human vaccines are aluminum-based compounds such as aluminum hydroxide or phosphates (alum).
(2) Description of the Related Art
This applies, in particular, to various vaccines in which the active principle consists of an antigen obtained by genetic recombination in vitro, such as Havrix, a hepatitis A vaccine in which the active principle is an antigen obtained from a hepatitis A virus strain cultured in cell culture, and containing aluminum hydroxide in the proportion of 1.5 mg per dose (0.5 mg of aluminum) and marketed by the company Smith Kline & French (6, Esplanade Charles De Gaulle, 92731 Nanterre Cedex), under the trade name Havrix. Two administrations performed at an interval of one month enable seroconversion to be induced in 98% of individuals.
Three recombinant vaccines against the hepatitis B virus are currently on the market; they are:
Genhevac B from Pasteur Merieux Serums et Vaccins (58, avenue Leclerc 69007 LYON FRANCE), which vaccine contains not more than 3.5 mg of aluminum hydroxide per dose, PA1 Engerix B marketed by Smith, Kline & French, containing 1.9 mg of aluminum hydroxide per dose, PA1 Recombivax HB marketed by Merck, Sharp and Dhome, containing 1.5 mg of aluminum hydroxide per dose. PA1 improving the immunogenic power of recombinant hepatitis B vaccines, PA1 the existence of a mixed hepatitis B+hepatitis A vaccine enabling an immunization against infection by both of these viruses to be obtained in a minimum number of injections, which is impossible at the present time on account of the immunizing power of the current hepatitis B vaccines, PA1 the possibility of immunizing nonresponder subjects, PA1 the possibility of establishing a prophylaxis after 1 or 2 injections in normal responders, PA1 the possibility of establishing a prophylaxis or an immunization when the active principle of the vaccine is a hapten or, more generally speaking, a molecule which it is difficult to make immunogenic.
The hepatitis B vaccines mentioned above are effective only after at least three injections at 0, 30 and 60 or 180 days, followed by an obligatory booster after one year; in addition, a number of subjects are poor responders or nonresponders. In the total population, they represent approximately 5%, and the capacity to obtain seroconversion depends greatly on the subject's age; it is already significantly smaller from 30-35 years onwards. Furthermore, there are groups which are especially poor responders, namely hemodialysis patients (30 to 45% of that population) and renal transplant recipients, 75 to 95% of whom do not respond to vaccines. Various investigations have studied this resistance to immunization with hepatitis B vaccines: the investigations of Stevens et al. (1), Zachoval et al. (2) and Grob PJ et al. (3) should be mentioned. This problem of lack of response to a hepatitis B vaccine becomes extremely serious in countries in which this viral infection has substantial endemic character and where approximately 5% of the population represents a considerable number of individuals; it is, in addition, especially critical in at-risk populations such as hemodialysis patients, who are rightly driven to undergo a large number of blood transfusions with the subsequent risks of viral contamination. Lastly, the fact of having to perform not less than three injections followed by a booster in order to immunize responder patients, the fourth injection coming one year after the first, represents an especially difficult and risky follow-up situation.
The problem of developing a vaccine which can, on the one hand, confer on existing nonresponders an immunization against a hepatitis virus infection, and, on the other hand, enable the number of vaccinating doses to be decreased in normal responders, permitting a follow up and a much more rigorous prophylaxis in regions where the infection is endemic or in at-risk populations, proves to be a medical necessity.
Another problem arising for the prophylaxis of hepatitis in regions where the infection is endemic is to produce a mixed vaccine against the different kinds of hepatitis, and in particular hepatitis A and B. At the present time, double vaccination against hepatitis A and B necessitates six injections, four of them for hepatitis B and two for hepatitis A; thus, the prophylaxis of hepatitis would be advantageously improved by: